Cytotoxic chemotherapies lose efficacy with subsequent rounds of therapy in the retreatment of follicular lymphoma, eventually leading to refractory disease, however the question remains whether the survival of patients with FL is improving with new treatment regimens.
In the current retrospective analysis, nine patients with relapsed grade 1 and 2 FL, responding to FCR regimen and consolidated with
90Y–RIT obtained a significant high rate of response with 100 % of CR and acceptable toxicity. The conversion from PR to CR was already shown in the published phase III study (FIT-study) in first-line FL [
3,
4] and also in phase II studies [
5‐
12] of consolidation with the radioimmunotherapy agent
131 I-tositumomab after first-line induction [
19,
20] thus, confirming the ability of
90Y-RIT to improve responses also in patients who are pretreated with rituximab based combination therapy [
3]; even if in our two patients there is no proof that this conversion was due to RIT and not to a late response to FCR. In the FIT study, close to 17 % of the patients in the control arm, converted from PR to CR during watchful waiting [
3], but our 2 patients who had higher risk of resistance already being pretreated must be considered.
In our analysis, the OS at 2 years was 89 %, at 3 years 76 % and at 4 years 61 % and OS and PFS are 67 % at 7.5 years. In another study conducted on patients with recurrent FL, treated with FCR, 75 % OS rate at 4 years and 61 % PFS rate at 4 years were registered, but in that study only 7 % of patients had been treated previously with rituximab and furthermore no patients had received combination treatment with chemotherapy plus rituximab [
21]. Furthermore our results are in line with those recently described in a Japanese study [
22] on 94 patients with relapsed or refractory low grade B cell non-Hodgkin lymphoma, among them 61 patients with grade 1 and 2 FL, treated with
90Y-RIT alone as salvage therapy and showing a CR rate of 69 %. In the Japanese cohort, during a median follow up of 46.5 months, the PFS rates of the first 50 patients who had undergone ≤ 2 and ≥ 3 previous regimens, and for those who achieved CR compared with those who did not were 38 and 11 months, respectively; the number of previous regimens and CR were statistically significant (
p = 0.0011 and
p < 0.0001, respectively). In our study 7/9 patients underwent ≤ 2 previous regimens before FCR and all of patients reached CR after
90Y-RIT with a PFS of 67 % at 7.5 years. Regarding AEs no grade 3 or 4 anemia was noted and no erythropoietic growth factors were used; there was high incidence of grade 3 or 4 neutropenia and thrombocytopenia but no platelet transfusions were necessary and granulocyte colony-stimulating factors were utilized in the majority of patients during FCR treatment and in all of them after
90Y–RIT. Despite the high incidence of grade 3 or 4 neutropenia, there were no patients requiring hospitalization for infection. We registered a case of herpes zoster infection after 8 months following valacyclovir discontinuation that disappeared after retreatment, and a case of fungal infection by
conidiobolus, developed 10 months after
90Y-RIT and disappeared with itraconazole treatment. Other previous studies have already shown the low percentage of patients requiring hospitalization for infections [
3,
15] and a favorable safety profile [
23,
24]. A case of t-MDS with complex karyotype was diagnosed 26 months after
90Y-RIT consolidation: this patient received 3 previous regimens before FCR plus
90Y-RIT and as already mentioned the patient died of sepsis. This patient had been previously treated with topoisomerase II inhibitors, alkylating agents and purine nucleoside analogs. Czuczman et al. reported incidence of t-MDS and t-AML (treatment-related acute myeloid leukemia) after
90Y–RIT of 0.3 % per year after the diagnosis of NHL and 0.7 % per year after treatment. Most patients with t-MDS or t-AML had multiple cytogenetic aberrations, commonly on chromosomes 5 and 7, suggesting an association with previous exposure to chemotherapy. In Czuczman study, these malignancies were diagnosed at a median of 5.6 years (range 1.4 to 13.9) after the diagnosis of NHL and 1.9 years (range 0.4 to 6.3) after radioimmunotherapy [
25]. The conclusion of this study was that the annualized incidences of t-MDS and t-AML were consistent with that expected in patients with NHL who had extensive previous chemotherapy and did not seem to increase after
90Y-RIT. However, in the FIT study 8 patients who developed MDS/AML were treated with
90Y-RIT, suggesting a role played by
90Y-RIT in the risk of secondary MDS/AML, thus it is reasonable to consider monitoring these patients closely. Cytogenetic testing before treatment with RIT may identify existing chromosomal abnormalities in previously treated patients, particularly those who have been treated with alkylating agents and purine analogs and would be at higher risk of developing t-MDS or t-AML.
In our series, the other two deaths were not related to progressive disease and all three deceased patients obtained CR before
90Y-RIT and died still in CR; so far the six survivors have maintained a high quality of life without having to make many visits to the hospital due to toxicity. Additional follow up is required to determine potential long-term AEs with
90Y-RIT consolidation. In our patients, the response to
90Y-RIT was assessed by CT, bone marrow biopsies and also with FDG-PET. This imaging procedure is useful to evaluate disease extension before treatment and response to RIT in FL. A study has shown that the post-
90Y–RIT PET result is an independent predictive factor of PFS [
26].